In this pilot cohort, PRS-based risk stratification led to earlier or more intensive screening recommendations in half of the participants, while family history also influenced management.
Abstract
Background Population-based mammographic screening is primarily age-based. However, breast cancer risk is multifactorial, and women may benefit from personalized risk-based screening. This pilot study aimed to explore the use of polygenic risk score (PRS) as a tool for risk stratification in personalized screening. Methods We included 80 women aged 40–49 years referred for clinical mammography. Exclusion criteria were prior breast cancer or premalignant breast disease, and previous genetic testing. After DNA collection, PRS was calculated from 2805 Single Nucleotide Polymorphisms (SNPs). Screening recommendations were based on each participant’s relative 10-year breast cancer risk estimated from PRS and compared with the 10-year risk of an average woman of the same age. Women with a self-reported family history of cancer meeting standard criteria were referred for gene panel testing for pathogenic variants in high-risk genes. A follow up questionnaire regarding participants’ experiences was distributed 6–9 months after PRS testing. Results Mean age was 45.2 years (SD 2.8). Mean relative 10-year breast cancer risk was 1.18 (SD 0.57). Based on PRS, 40 participants were recommended standard biennial screening 50–69 years, while 40 were advised to begin biennial screening before age 50. Among these, 7 were recommended annual mammography from when their 10-year risk reached twice that of an average 50-year-old. Twenty-one women underwent gene panel testing; no pathogenic variants in breast cancer genes were identified. Five women were advised annual mammography from 40–60 years due to family history of breast cancer, regardless of PRS. Most respondents viewed breast cancer risk assessment positively and did not report increased anxiety after testing. Conclusions In this pilot cohort, PRS-based risk stratification led to earlier or more intensive screening recommendations in half of the participants, while family history also influenced management.
This study identified several personal characteristics that were more strongly linked to breast cancer occurrence, highlighting the value of integrating clinical and self-reported information to better understand individual risk and support more targeted prevention and screening efforts.
M. Franchini, F. Denoth, Stefania Pieroni et al.· Cancers· 0 citations
Hereditary breast cancer accounts for approximately 10% of all breast cancer cases. Swedish national breast cancer guidelines specify criteria for germline genetic testing. This quality review aimed to investigate the adherence to these criteria at diagnosis of breast cancer, the prevalence of pathogenic variants and the impact on surgical management.
All patients diagnosed with primary breast cancer between July 2023 and June 2024 at Karolinska University Hospital were identified through the Swedish National Quality Register for Breast Cancer. Clinical data was collected from medical records for four groups fulfilling testing criteria: age £40 years, age ≤50 years with bilateral breast cancer or strong family history, patients with triple negative breast cancer (TNBC) and male patients.
Among 630 identified patients, 138 (22%) met at least one testing criterion. Gene panel testing was completed for 114 patients (87%), and pathogenic variants were detected for 13/114 (11%). Variants were most frequently detected in patients with TNBC (15%), followed by those aged ≤50 years with bilateral disease or strong family history (11%) and those aged ≤40 years (7%), while no variants were found in the male patient. CanRisk risk prediction was performed for 47/114 tested patients (41%). Genetic findings and risk assessment by CanRisk led to modified primary surgical management for 15 patients, with bilateral mastectomy performed in 14 of these cases.
Adherence to national guidelines for genetic testing was high. Pathogenic variants were identified in 11% of the patients, and the results had a substantial impact on surgical decision-making.
Bi-Ying Huang, Anne Kinhult Stålbom, Svetlana Bajalica Lagercrantz et al.· British Journal of Surgery· 0 citations
IMPORTANCE
Patients diagnosed with breast cancer (BCa) are at increased risk of multiple common diseases; however, the spectrum of these diseases and the contribution of inherited genetic susceptibility remain incompletely characterized.
METHODS
We evaluated 15 common diseases and tested their associations with BCa exposure and disease-specific polygenic risk scores (PRS) in the UK Biobank (UKB; N = 254,736). Analyses were performed using cause-specific Cox proportional hazards models within a full-cohort framework, with time-updated BCa status, delayed entry at study recruitment, and age as the underlying time scale.
RESULTS
After recruitment, incident BCa was diagnosed in 11,386 women (4.47%), including 2,742 (24.08%) with metastatic BCa. Patients with BCa had an increased risk of nine diseases spanning cardiovascular, metabolic, and neuropsychiatric domains (P<0.003, Bonferroni-corrected). Elevated risks were generally observed among patients with both early staged and advanced BCa. Inherited susceptibility further stratified disease risk, with the highest risks observed among patients with BCa with elevated disease-specific PRS. For example, compared with women without BCa, the hazard ratio (HR; 95% CI) for osteoporosis was 2.33 (2.15-2.52) among women with any BCa, 2.38 (2.18-2.59) among those with non-metastatic BCa, and 2.12 (1.78-2.54) among those with metastatic BCa; the HR was 4.48 (3.99-5.02) among patients with BCa in the highest quartile of osteoporosis-specific PRS (all P<0.001). In contrast, BCa was not significantly associated with risk of coronary artery disease.
CONCLUSION
BCa and inherited genetic susceptibility jointly contribute to increased risk of multiple common diseases, supporting the integration of genetic risk stratification into survivorship care.
Annabelle Ashworth, Zhu-Qing Shi, Huy Tran et al.· JNCI Cancer Spectrum· 0 citations
To evaluate temporal changes in breast cancer lifetime risk (BC-LTR) over a 10-year period among women with clinically elevated risk but without known pathogenic genetic mutations, using the International Breast Cancer Intervention Study (IBIS) breast cancer risk evaluation tool, and to assess implications for personalised surveillance strategies. In this retrospective study, women referred for elevated risk assessment in 2014 underwent BC-LTR estimation using IBIS (v8.0b). Risk was recalculated in 2024 using the same model without recalibration. Women who developed breast cancer, underwent bilateral mastectomy, died during follow-up, were older than 85 years in 2024, or carried pathogenic genetic mutations were excluded, as IBIS BC-LTR recalculation is not applicable in these contexts. Risk factor temporal changes were evaluated using paired statistics. A linear mixed model assessed predictors of IBIS BC-LTR and their association with temporal changes. Among 362 eligible women, mean IBIS BC-LTR decreased from 23% in 2014 to 19% in 2024 (mean absolute change = 6.5, p < 0.001). Risk group reclassification occurred in 44%: 36% shifted to a lower risk category and 8% to a higher category. Increase in IBIS BC-LTR was associated with increasing density (p < 0.0001), higher BMI (p = 0.002), current HRT use (p = 0.007), and additional affected relatives (p < 0.03), whereas downward reclassification was mainly linked to decreasing density (p < 0.0001). IBIS BC-LTR estimates change over time in women with elevated clinical risk. Periodic reassessment may better align estimated risk with tailored screening strategies, supporting more precise, individualised surveillance. Variation in IBIS BC-LTR scores over time highlights the need for periodic recalculation to improve individual risk stratification and guide more appropriate, personalised imaging and screening pathways. Breast cancer risk models identify women most likely to benefit from supplemental screening. IBIS BC-LTR estimates changed over 10 years, reclassifying over 40% of women with elevated baseline risk into a different risk category. Periodic IBIS BC-LTR recalculation is essential to optimise risk stratification and screening pathways. Breast cancer risk models identify women most likely to benefit from supplemental screening. IBIS BC-LTR estimates changed over 10 years, reclassifying over 40% of women with elevated baseline risk into a different risk category. Periodic IBIS BC-LTR recalculation is essential to optimise risk stratification and screening pathways.
M. Keupers, Sam Nijssen, Willem Sarkol et al.· Insights into Imaging· 0 citations
BACKGROUND
National guidelines recommend English women between 30 and 49 years with moderate/high risk of breast cancer (BC) be offered screening and prevention interventions. Identification largely relies on family history-based criteria amongst women self-presenting in primary care. We aimed to understand the preference for different potential risk assessment strategies in this population.
METHODS
A cross-sectional survey including a discrete choice experiment. Risk assessments were defined using six attributes, including initiation strategy, eligibility for a full/detailed risk assessment, components of the risk assessment, including multifactorial risk assessment based on the BOADICEA/CanRisk model, and sensitivity. Coefficients from conditional logistic regression were used to estimate preference for different risk assessment approaches compared to current care.
RESULTS
Participants (n = 893) preferred alternative approaches for risk assessments over current care, particularly where all eligible women were proactively invited and more above-average risk women were correctly identified. All but one of 21 risk assessment approaches was preferred, with the most favoured approaches having a probability of being preferred over current care >92%. Education level and ethnicity potentially impacted the strength of participant priorities.
CONCLUSIONS
Offering multifactorial BC risk assessments to younger women in primary care, especially the most proactive and broad approaches, would be acceptable and preferred over current practice.
Rebecca A. Dennison, Maria Valasaki, S. Wright et al.· British Journal of Cancer· 0 citations
PURPOSE Recommendations for clinical management of women with germline pathogenic variants (PVs) in breast cancer susceptibility genes vary by gene. The goal of this study was to examine the utilization of risk-reducing strategies and treatments in women with germline PVs in breast cancer susceptibility genes. METHODS This cross-sectional study identified women with a PV in at least one of 13 breast cancer susceptibility genes from germline panel testing at a single commercial laboratory between 2015 and 2023. Paired health care claims data for 12 months after genetic testing were evaluated to estimate the utilization of risk-reducing mastectomy and salpingo-oophorectomy, breast magnetic resonance imaging (MRI), and pancreatic screening (magnetic resonance cholangiopancreatography or endoscopic ultrasound) in these women. Multivariable logistic regression models were used to evaluate the association of clinicodemographic factors and genetic testing results with intervention utilization. RESULTS Of 3,959 women with a PV (2,088 cancer-free; 1,871 with primary breast cancer diagnosed ≤120 days before genetic testing), the average age at testing was 45 years, 67% were White, and 90% reported a family history of cancer. Breast MRI was used by 33% of cancer-free women and 31% of women with breast cancer after genetic testing; pancreatic screening occurred in <11% of the eligible population. Women with PVs in BRCA1/2 versus other breast cancer susceptibility genes had higher odds of risk-reducing mastectomy (cancer-free: odds ratio 7.2 [95% CI, 3.5 to 14.5]; with cancer: 6.0 [95% CI, 4.2 to 8.5]) and salpingo-oophorectomy (cancer-free: 7.2 (95% CI, 4.6 to 11.3]; with cancer: 13.8 [95% CI, 9.7 to 19.7]). CONCLUSION Utilization of risk-reducing surgery was highest in women with BRCA1/2 PV. Pancreatic screening was low in all patients. Future studies are needed to examine the factors underlying these trends.
Emily M. Russell, S. Nielsen, R. Ellsworth et al.· JCO Precision Oncology· 0 citations
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